Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=O)[C:10](=[O:21])[CH:9]=2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH2:72])=[N:68]2)[CH2:63][O:62]1>CN(C)C=O.C(OCC)(=O)C>[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH:72][C:14](=[O:16])[C@@H:13]([N:11]3[CH2:12][C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=4)=[CH:9][C:10]3=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:68]2)[CH2:63][O:62]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: COc1ccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A solution of (S)-2-[4-(4-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.36 g, 1.14 mmol) in N,N-dimethylformamide (4.41 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.57 mL, 3.44 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.76 g, 1.72 mmol) and a solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.24 g, 1.26 mmol) in N,N-dimethylformamide (0.5 mL). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (50 mL) and was washed with a saturated aqueous ammonium chloride solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 50-100% ethyl acetate/hexanes) afforded (S)-2-[4-(4-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.38 g, 68%) as a white solid: HR-ES-MS m/z calculated for C26H34N4O6 [M+H]+ 499.2551, observed 499.2551; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.45 (br. s., 1H), 1.50-1.63 (m, 1H), 1.63-1.82 (m, 1H), 3.67-3.76 (m, 1H), 3.77 (s, 3H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.05-4.22 (m, 3H), 4.28-4.41 (m, 1H), 4.53 (d, J=18.1 Hz, 1H), 4.75 (s, 1H), 4.88 (dd, J=10.7, 4.7 Hz, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.00 (d, J=8.9 Hz, 2H), 7.23 (d, J=8.9 Hz, 2H), 7.60 (d, J=2.1 Hz, 1H), 10.78 (s, 1H).
Reaction SMILES: O[Li].[OH2:3].[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[NH:8][C:9]1[C:10]2[CH:19]=[C:18](OCC)[NH:17][C:11]=2[NH:12][C:13](=C=O)[N:14]=1.Cl.[CH3:27][OH:28]>O>[C:27]([C:18]1[NH:17][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:7]3[CH:23]=[CH:24][CH:25]=[C:5]([Cl:4])[CH:6]=3)[C:10]=2[CH:19]=1)([OH:28])=[O:3]
Reactant: CO
Reactant: CCOc1cc2c([nH]1)NC(=C=O)N=C2Nc1cccc(Cl)c1
Reactant: O
Agent: Cl
Agent: [Li]O
Product: O=C(O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reaction time: 4.5 h

Procedure:
A solution of 25 mg (0.6 mmol) of LiOH.H2O in 0.4 ml of H2O is added dropwise to a suspension of 95 mg (0.30 mmol) of 4-(3-chloroanilino)-6-ethoxy-carbonyl-7H-pyrrolo[2,3-d]pyrimidine (see stage1.4) in 0.7 ml of methanol and the mixture is heated to boiling for 4.5 h. It is cooled in an ice bath and acidified with 0.6 ml of 1 normal HCl solution. Filtering off and washing with water yields 6-carboxy-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=8.7; FAB-MS: (M+H)+=289.
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[C@H:3]2[NH:13][C:14]([NH:16][C@@H:2]12)=[O:15].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[C:50]([NH:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][NH2:66])([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>CN(C=O)C>[C:50]([NH:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][NH:66][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][C@H:4]1[C@@H:3]2[C@@H:2]([NH:16][C:14]([NH:13]2)=[O:15])[CH2:1][S:5]1)([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: CC(C)(C)OC(=O)NCCOCCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A solution of vitamin H (Biotin) (2.2 g, 9 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (3 g, 8 mmol), and DIPEA (1.8 mL, 10 mmol) in DMF (100 mL) was stirred for 10 minutes at room temperature before being adding dropwise to a solution of N-Boc-3,6-dioxaoctane-1,8-diamine (1.5 g, 6 mmol, 1). The reaction mixture was stirred for 1 hour at room temperature, after which the DMF was removed in vacuo to give an oily residue, which was purified by flash silica gel column chromatography (CH2Cl2/CH3OH, 25/1, v/v) to afford N-Boc-N′-biotinyl-3,6-dioxaoctane-1,8-diamine (2.0 g, 90%). 1H NMR (300 MHz, CD3OD): δ 4.5 (m, 1H), 4.3 (m, 1H), 3.6 (s, 4H), 3.54 (tt, 4H), 3.39 (t, 2H), 3.26 (t, 2H), 2.9 (dd, 1H), 2.7 (d, 1H), 2.2 (t, 2H), 1.7-1.5 (m, 8H), 1.4 (s, 9H); MALDI HRMS: m/z 497.2416 [M+Na+]. Calcd for C21H38N4NaO6S 497.2410.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([O:17][CH3:18])[CH:8]=[C:9]([CH:12]3OCC[O:13]3)[CH:10]=2)[O:5][C:4]([CH3:20])([CH3:19])[CH:3]=1.C(=O)=O.C([Li])CCC.S([Cl:33])(C)(=O)=O>C1COCC1>[Cl:33][C:2]1[C:11]2[C:6](=[C:7]([O:17][CH3:18])[CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[O:5][C:4]([CH3:20])([CH3:19])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C2OCCO2)cc2c1OC(C)(C)C=C2Br
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)cc2c1OC(C)(C)C=C2Cl
Temperature: 0 °C

Procedure:
366 mg of 4-bromo-6-[1,3]dioxolan-2-yl-8-methoxy-2,2-dimethyl-2H-chromene (1.07 mmol) was dissolved in 4 ml of abs. THF and treated at −78° (dry-ice bath) with 0.735 ml n-butyl lithium (1.6M, n-hexane, 1.1 eq.). 15 min. later, 0.114 ml of mesyl chloride (1.1 eq.) was added and the dry-ice bath replaced by an ice-bth. After 30 min. the reaction mixture was poured onto crushed ice/concentrated HCl and vigorously stirred to cleave the acetal. Twofold extraction with ether, washing with NaCl, drying over magnesium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2 with n-hexane/AcOEt=87/13) to yield 77 mg of the title compound as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1F.Cl>CN1C(=O)CCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[C:8]([O:14][C:28]2[CH:27]=[C:26]([Cl:29])[CH:25]=[CH:24][C:23]=2[Br:22])[CH:7]=1)[CH3:2]
Reactant: Fc1cc(Cl)ccc1Br
Reactant: CCOC(=O)Cc1ccc(CC)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1ccc(CC)c(Oc2cc(Cl)ccc2Br)c1
Temperature: 120 °C

Procedure:
step 1—To a solution of ethyl 4-ethyl-3-hydroxyphenylacetate (12a, 1.000 g; 4.8 mmol) and NMP (10 mL) was added K2CO3 (1.99 g; 14.4 mmol) and 1-bromo-4-chloro-2-fluorobenzene (1.106 g; 5.28 mmol). The reaction was heated to 120° C. and monitored by TLC. After 8 h the reaction was cooled to RT and 10% HCl was added. The mixture was extracted with EtOAc and the combined extracts were washed with H2O and brine. The extracts were dried (Na2SO4) filtered and evaporated. The crude product was chromatographed with SiO2 and eluted with a gradient of hexane/EtOAc (100:0 to 60:40) to afford [3-(2-bromo-5-chloro-phenoxy)-4-ethyl-phenyl]-acetic acid ethyl ester.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH2:40]([N:47]1[CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=[N:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:40]([N:47]1[CH:51]=[C:50]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:49]=[N:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 95.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (200 mg, 0.303 mmol) was coupled with 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 15) (130 mg, 0.455 mmol) using sodium carbonate (81 mg, 0.759 mmol) and Pd(PPh3)2Cl2 (11 mg, 0.015 mmol) in toluene/ethanol/water (10/2/1 ml) to afford 200 mg (95.6% yield) of titled compound after purification by column (Silica gel 6/120) using 50% EtOAc/hexane as eluent. MS: m/z=689.3 (M+1).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:21][S:22]([C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][CH:26]=1)(=[O:24])=[O:23]>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[S:29][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][N:27]=3)[CH2:31][CH2:32]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3ncc(S(C)(=O)=O)s3)CC2)c1
Yield: 38 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example A4) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 38%). MS (m/e): 514.3 (M+H+, 100%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][N:15]=1.[CH3:17][O:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)C>CN(C)C=O>[CH3:17][O:18][CH2:19][CH2:20][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][N:15]=1
Reactant: Nc1nccnc1-c1nc2ccccc2[nH]1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCn1c(-c2nccnc2N)nc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.4 %

Procedure:
3-(1H-benzimidazol-2-yl)pyrazin-2-amine (0.302 g, 0.14 mmol) was dissolved in N,N-dimethyl formamide (10 mL) and treated with 2-bromoethyl methyl ether (0.15 mL, 0.16 mmol) and cesium carbonate (0.475 g, 1.4 mmol). The mixture was stirred at ambient temperature for 20 hours and then filtered through celite. The filtrate was concentrated and partitioned between ethyl acetate and water. The mixture was extracted into ethyl acetate (×3) and the combined organic layers were washed with water, and then with saturated sodium chloride. The organics were dried over magnesium sulfate, filtered and concentrated. Trituration with diethyl ether afforded the title compound as tan solids (0.275 g, 0.10 mmol).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C[O-].[Na+].Cl[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)=[CH:12][C:13]#[N:14]>CO>[CH3:6][O:5][C:1]([C:2]1[S:3][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:12][C:13]=1[NH2:14])=[O:4]
Reactant: N#CC=C(Cl)c1cccc(Cl)c1
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc(-c2cccc(Cl)c2)cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium pellets were slowly added to methanol solution to form NaOMe in situ, then methyl thioglycolate was added over a period of 20 minutes to the methanol solution. A solution of 3-Chloro-3-(3-chloro-phenyl)-acrylonitrile in methanol was added slowly and was brought to reflux for 1 hour. The reaction mixture was cooled to room temperature and methanol was concentrated to 100 mL and 200 mL of water was added, stirred for 30 min and the yellow precipitate was collected and washed with water several times to yield a yellow crystalline compound, mp 92-95° C. 1H NMR (DMSO-d6) δ1.60 (s, 6H), 7.30 (d, 1H, J=8.41 Hz), 7.41 (d, 1H, J=8.41 Hz), 10.47 (s, 1H); MS (+APCI) m/z 213(M+H); Anal. Calc. For C9H9ClN2O2: C, 50.84; H, 4.27; N, 13.17. Found: C, 50.99; H, 4.28; N, 12.98.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([N:19]=[N:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.C(O)C.[OH-].[Na+].Cl>C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([N:19]=[N:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(N=Nc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)azo]-benzoate (Compound 46a) 16.5 mg, 0.042 mmol) in THF (2 ml) and ethanol (1 ml) was added 80.0 mg (2.00 mmol) of NaOH (2.0 ml, 1M aqueous solution). The mixture was stirred for 12 hours at room temperature, acidified with 10% HCl, and extracted with EtOAc. The combined organic layers were washed with water, and saturated aqueous NaCl, then dried over MgSO4. Removal of the solvents under reduced pressure, and recrystallization of the residue from EtOAC/hexane, afforded the title compound as a red solid. 1H NMR (acetone-d6): δ 8.19 (2H, d, J=8.4 Hz), 7.92 (2H, d, J 8.5 hz), 7.88 (2H, dd, J=2.1, 6.1 Hz), 7.66 (1H, s), 7.64 (2H, d, J=2.3 Hz), 7.28 (4H, d, J=3.0 Hz), 6.09 (1H, t, J=2.5 Hz), 2.42 (2H, d, J=4.8 Hz), 2.39 (3H, s), 1.40 (6H, s).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N+:10]([C:13]1[CH:14]=[C:15]([C@@H:19]([OH:22])[CH2:20][CH3:21])[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[S:24]([O:22][C@H:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=1)[CH2:20][CH3:21])(=[O:26])(=[O:25])[CH3:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@H](O)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](OS(C)(=O)=O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
Diisopropylethylamine (1.07 g, 8.3 mmol) is added to a mixture of (S)-1-(3-nitrophenyl)propanol (XXI, PREPARATION 1, 1 g, 5.5 mmol) in methylene chloride (20 mL). The mixture is cooled to −20° and methanesulfonyl chloride (0.69 g, 6.02 mmol) is added. The reaction is held at −20° for 10 min, then held at 0° for 40 min. The reaction is diluted with methylene chloride, sodium bicarbonate (5%) is added and the phases are separated. The methylene chloride is evaporated to give the title compound, [α]D=−79.9° (ethanol, c=1); TLC (silica gel GF, ethyl acetate/hexane, 20/80) Rf=0.19; NMR (CDCl3, TMS) 0.96-1.01, 1.88-2.17, 2.89, 5.54-5.59, 7.57-7.62, 7.70-7.73 and 8.20-8.24 δ.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[C:9]([N:11]1[CH2:16][CH:15]([CH2:17][CH3:18])[O:14][C:13]2[CH:19]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[N:27][CH:28]=3)[CH:21]=[CH:22][C:12]1=2)=[O:10].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:17]([CH:15]1[O:14][C:13]2[CH:19]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[N:27][CH:28]=3)[CH:21]=[CH:22][C:12]=2[N:11]([C:9](=[O:10])[NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16]1)[CH3:18]
Reactant: CCC1CN(C(=O)Cl)c2ccc(-c3ccc(OCC(C)(C)C(=O)OC)nc3)cc2O1
Reactant: CCCCCCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCNC(=O)N1CC(CC)Oc2cc(-c3ccc(OCC(C)(C)C(=O)OC)nc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
n-Hexylamine (23.0 μL, 0.173 mmol) was added dropwise to a solution of methyl 3-(5-(4-(chlorocarbonyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-11 (50.0 mg, 0.115 mmol) and N-ethyl-N,N-diisopropylamine (40.2 μL, 0.231 mmol) in anhydrous methylene chloride (1.10 mL) at 0° C. under an atmosphere of argon. The reaction mixture was slowly warmed to room temperature and stirred for 8 h, then sequentially diluted with methylene chloride (30 mL), quenched with an aqueous pH 7 phosphate buffer solution (15 mL) and decanted. The aqueous layer was extracted with methylene chloride (3×30 mL); the combined extracts were successively washed with an aqueous pH 7 phosphate buffer solution (20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. Crude methyl 3-(5-(2-ethyl-4-(hexylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-12 (55.2 mg, Yield=96%) was obtained as a light tan solid and was used for the next step without further purification. MS (ESI) [M+1]+ 498.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[NH:17][C:18](=[NH:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:25]=[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: CCCCCCC(=N)NO
Solvent: Cc1ccccc1
Product: CCCCCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Reaction time: 1.25 h

Procedure:
To a solution of 0.63 g (2.08 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 6 mL of toluene, 0.540 g (3.33 mmol) of 1,1-carbonyldiimidazole was added in portions at 25° C. to 30° C. under inert atmosphere. To the thickened mixture, 5 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of N-hydroxy-heptanimidamide (compound of Example 41; 0.9 g, 6.2 mmol) in 5 mL of toluene was added to the above reaction mixture at 25° C. to 30° C. The reaction mixture was stirred at 25° C. to 30° C. under nitrogen for 12-14 h, followed by stirring at 100° C. to 105° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and quenched with 10 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 5 mL of toluene. The organic layers were combined and washed with 10 mL of 1N HCl solution, 10 mL of 5% sodium bicarbonate solution and 10 mL of 10% sodium chloride solution. The organic layer was distilled completely to obtain a crude residue, which was purified using column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[C:13]([F:19])([F:18])C(OC)=O.[F-:20].[K+].CN(C=O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[N+:9]([C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[C:13]([F:19])([F:20])[F:18])([O-:11])=[O:10]
Reactant: Cc1ccc(Br)c([N+](=O)[O-])c1
Reactant: COC(=O)C(F)(F)Cl
Reactant: [F-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 48 h
Yield: 57 %

Procedure:
A mixture of 6.00 g (27.8 mmol) of 4-bromo-3-nitrotoluene, 5.86 mL (8.03 g, 55.6 mmol) of methyl chlorodifluoroacetate, 1.93 g (33.4 mmol) of potassium fluoride, 5.31 g (27.8 mmol) of cuprous iodide, and 25 mL of dry DMF was stirred at 110° C. for 2 days. The cooled material was diluted with aqueous citric acid and extracted 3× with ethyl acetate. The combined organic extracts were washed with H2O, then with brine, and dried over anhydrous Na2SO4. The residue obtained upon concentration of the filtered solution was flash chromatographed 3× on silica gel (elution with 100:1 and 25:1 hexane-EtOAc) to give 3.25 g (57%) of the title compound as a yellow liquid; homogeneous by TLC in 4:1 hexane-EtOAc; mass spectrum (EI) m/e 205 (M+). 400 MHz 1H NMR (CDCl3) δ2.48 (s, 3H), 7.49 (d, J=8 Hz, 1H), 7.67 (s, 1H) overlapping 7.68 (d, J=8 Hz, 1H).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:15]=[C:16](C)[CH:17]=[CH:18][CH:19]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/[C:25](C)=[O:26])=N\O.C(=O)C1C=CC=C(OC)C=1>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:26][CH3:25])[CH:15]=2)[O:6][C:7]=1[CH3:8]
Reactant: CC(=O)/C(C)=N/O
Reactant: Cc1cccc(-c2nc(CI)c(-c3ccccc3)o2)c1
Agent: COc1cccc(C=O)c1
Product: COc1cccc(-c2nc(CI)c(C)o2)c1

Procedure:
Analogous to the building block synthesis of 4-iodomethyl-5-phenyl-2-m-tolyloxazole, diacetylmonoxime and m-anisaldehyde gave 4-iodomethyl-2-(3-methoxyphenyl)-5-methyloxazole.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([NH:16][C:17](=[O:32])[C:18]([F:31])([F:30])[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([F:29])=[CH:21][CH:20]=2)[C:8]=1[F:33])(=[O:3])[CH3:2]>C(O)C.C1COCC1.[Pd]>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:8]([F:33])=[C:9]([NH:16][C:17](=[O:32])[C:18]([F:30])([F:31])[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([F:29])=[CH:21][CH:20]=2)[CH:10]=[CH:11][C:12]=1[NH2:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1c([N+](=O)[O-])ccc(NC(=O)C(F)(F)c2ccc(F)c3ccccc23)c1F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)OCCc1c(N)ccc(NC(=O)C(F)(F)c2ccc(F)c3ccccc23)c1F
Reaction time: 5 h
Yield: 83.3 %

Procedure:
A mixture of 2-{3-[2,2-difluoro-2-(4-fluoronaphthyl)acetylamino]-2-fluoro-6-nitrophenyl}ethyl acetate (4.9 g, 10.5 mmol), as prepared in the preceding step, and Pd/C (10%, 500 mg) in ethanol (50 mL) and THF (50 mL) was stirred under hydrogen for 5 hours. The reaction mixture was filtered through Celite, and washed with THF and MeOH. The filtrate and washings were combined, concentrated in vacuo, and flash chromatographed on silica gel eluting with EtOAc/DCM (0 to 2%) to produce the title compound (3.8 g, 83%) as an off white solid. 1H-NMR (400 MHz, CDCl3) δ 8.27 (d, J=8.2 Hz, 1H), 8.19 (d, J=8.6 Hz, 1H), 8.10 (s, 1H), 7.82 (m, 2H), 7.63 (m, 2H), 7.19 (t, J=8.6 Hz, 1H), 6.46 (d, J=8.7 Hz, 1H), 4.19 (t, J=7.4 Hz, 2H), 4.08 (s, 2H), 2.91(t, J=7.3 Hz, 2H), 2.08 (s, 3H).
Reaction SMILES: CO.C([NH:10][C:11]1[C:16]([F:17])=[C:15]([CH3:18])[C:14]([F:19])=[C:13]([F:20])[N:12]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[NH2:10][C:11]1[C:16]([F:17])=[C:15]([CH3:18])[C:14]([F:19])=[C:13]([F:20])[N:12]=1
Reactant: Cc1c(F)c(F)nc(NCc2ccccc2)c1F
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(F)c(N)nc(F)c1F
Reaction time: 24 h

Procedure:
To 4 ml of methanol were added all amount of the crude 2-benzylamino-3,5,6-trifluoro-4-methylpyridine as described above together with 0.18 g of 10% palladium on carbon and 2 ml of acetic acid, and the mixture was hydrogenated at 50° C. for one day. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure to obtain 1.35 g of the title compound as a colorless solid.